SUMMARY What is the right way to investigate neuronal circuits? The dominant strategy in neuroscience is to examine the relationships between stimuli, brain signals and behavior. In this framework, the investigator is in a privileged situation. Because s/he has access to both brain patterns and signals outside the brain, s/he can establish correlations between them. However, without further ?grounding?, it remains unknown whether these experimenter-observed correlations are actually utilized by the brain. The present project will take an alternative approach by investigating how neuronal population patterns in an upstream circuit are ?read out? by a downstream observer circuit/mechanism in memory circuits. Using this strategy, we will investigate how neuronal activity is transformed at each stage in the entorhinal cortex (EC) ? dentate gyrus (DG) ? CA2/3 ? CA1- neocortex loop, and relate such transformations to behavior. The projects will combine large-scale electrophysiology, optogenetics and imaging in behaving rodents. Project 1 will examine the distinct contributions of medial and lateral entorhinal cortex (MEC, LEC) to spatial versus object learning, and will link behavior to EC-DG transmission of theta-gamma oscillatory patterns. Project 2 will examine information transmission within the dentate gyrus and across EC-DG-CA3 synapses. We will first quantify changes in LFP and spike-LFP coupling to test the contributions of EC and DG granule cell input to the firing patterns of DG mossy and CA3 pyramidal cells. We will then test whether DG granule and mossy cell replay is coordinated with hippocampal sharp wave ripples or with EC cell assemblies during post-experience sleep. Finally, we will test whether optogenetic manipulation of dentate spikes affects memory and induces re-configuration of CA3 networks. Project 3 examines whether distinct neuronal trajectories, such as forward and reversed sequences, are read out differentially by target circuits in the CA3-CA1 and CA1-parietal cortical circuits. Finally, Project 4 will test whether different hippocampal patterns are translated to distinct neocortical functional maps and whether such maps are modified by learning. Our ?reader-centric? approach will establish how neuronal patterns are transformed in the entorhinal- hippocampal-entorhinal loop, providing critical insights into physiological mechanisms of learning and memory and relevant diseases.